ISOLATION AND STRUCTURAL ELUCIDATION OF SACUBITRIL SODIUM DEGRADATION PRODUCTS BY MASS AND NMR SPECTROSCOPY

Abstract

As per ICH Q1A (R2), stress testing (i.e., acidic, basic, oxidative, thermolytic, hydrolytic, and photolytic) was carried out at room temperature with a single batch of Sacubitril Sodium of the drug substance. Though the drug is resistant to oxidation, thermal, and photolysis conditions, two degradation products were formed during base stress. By using gradient preparative HPLC and a normal C-18 column, the degradants were separated, and the obtained SAC D-1 and SAC D-2 were precisely characterized by LCMS and extensive NMR (including 2D) spectroscopic methods. Study of NMR spectra (1D, 2D) and Mass spectrometry confirmed the suggested structures for the products 5-([1,1'-biphenyl]-4-yl)-4-(3-carboxy propanamide)-2-methyl pentatonic acid (SAC D-1) and (3S)-5-([1,1'-biphenyl]-4-ylmethyl)-3-methyl pyrrolidin-2-one (SAC D-2).